ABSTRACT The goal of this investigation is to identify and characterize the role of microRNAs (miRNA) in serum exosomes on the risk of Systemic Lupus Erythematosus (SLE), and among patients with SLE, the risk of, and rate of progression to, lupus nephritis (LN). SLE is a prototypic autoimmune disease that is characterized by the presence of antinuclear autoantibodies, complement activation and multisystem organ damage, including LN, which accounts for significant morbidity and mortality particularly among persons of African American and Amerindian ancestry. The basis for this disparity remains poorly understood. Although the etiology of SLE is unclear, combinations of genetic and environmental factors play a causal role. Despite the discovery of several SLE susceptibility loci, variation in DNA sequence alone accounts for only a small fraction of common complex disease and efforts to utilize these markers to classify or monitor SLE clinical course, and the development of LN, have not yet been successful. Recent advances in transcriptome sequencing offer new opportunities to characterize miRNAs as novel biomarkers, which could significantly change the paradigm of SLE clinical monitoring. We will test the overarching hypothesis that distinct serum exosome miRNAs will correlate with the presence of SLE and among patients with SLE, the presence of and time to, LN, and that miRNAs influence the severity and rate of progression of LN by altering target gene expression. We intend to capitalize on a unique opportunity to explore these relationships in a large, ancestry diverse, well-characterized population of established SLE while taking advantage of recent advances in bioinformatics and whole transcriptome sequencing. Our objective to characterize the influence of exosome miRNAs relative to the risk of SLE and among these patients, the risk and tempo of LN in paired blood and target tissue fills a critical gap in knowledge required to advance efforts to detect, prevent and manage LN among SLE patients, as well as to identify new therapeutic targets. Findings forthcoming from this investigation will fill a critical gap elated to the disparate trends of SLE etiology and progression, which differ by ancestry, and may translate to other kidney phenotypes including those observed in immune-mediated cancers.